GABA is important to several neurological disorders, including Parkinson's disease, Huntington's chorea, Alzheimer's disease, and epilepsy, a central nervous system disease characterized by recurring convulsive seizures.
A deficiency of GABA in the brain has been implicated as one cause for convulsions. (Karlsson, A.; Funnum, F.; Malthe-Sorrensen, D.; Storm-Mathisen, J. Biochem Pharmacol 1974, 22, 3053-3061.) In an effort to raise the concentration of GABA in the brain, both direct injection and oral administration of GABA have been studied. It was shown that injection of GABA into the brain has an anticonvulsant effect, but it is obviously not a practical method. Taking GABA orally, however, is not effective because GABA cannot cross the blood-brain barrier, a membrane protecting the CNS from xenobiotics in the blood.
To correct the deficiency of brain GABA and therefore stop convulsions, an important approach is to use an inhibitor of GABA-aminotransferase (GABA-AT) that is able to cross blood-brain barrier. (Nanavati, S. M.; Silverman, R. B. J. Med. Chem. 1989, 32, 2413-2421.). Inhibition of this enzyme increases the concentration of GABA in the brain, which has therapeutic applications in epilepsy as well as other neurological disorders. One of the most effective in vivo time-dependent inhibitors of GABA-AT is 4-amino-5-hexenoic acid, which is also termed gamma-vinyl GABA or vigabatrin, an anticonvulsant drug marketed almost all over the world.
Other ways for correcting the deficiency of brain GABA relies on increasing GABA transmission by blocking GABA transporters like tiagabine, acting at GABA receptors (topiramate or felbamate) or activating the glutamate decarboxylase to increase GABA synthesis (pyridoxal phosphate, valproate, gabapentin). All strategies have in common to increase the concentration of GABA in the brain or directly activate its receptors and thus stimulate GABA therapeutic effects in various neurological disorders including epilepsy.
Regarding more particularly epilepsy, even though existing antiepileptic drugs can render 80% of newly diagnosed patients seizure free, a significant number of patients have chronic intractable epilepsy causing disability with considerable socioeconomic implications.
Anti-epileptic drugs are available for treating epilepsies, but these agents have a number of shortcomings. For instance, the agents are often poorly soluble in aqueous and biological fluids or are extremely hygroscopic. Of even greater importance is that patients often become refractory to a drug over time. In addition, many anti-epileptic agents cause unwanted side effects, neurotoxicities, and drug interactions. Even while being treated with one or a combination of the anti-epileptic drugs currently in clinical use, 30% of epileptic patients still experience seizures. As more anti-epileptic drugs are developed, the clinician will have expanded pharmaceutical options when designing an effective treatment protocol for each patient.
Vigabatrin, which was developed as an inhibitor of gamma-aminobutyric acid transaminase, was one of the most promising novel anticonvulsant active ingredients. However, vigabatrin, like some other compounds that increase GABA levels, can induce highly severe undesirable effects, such as an irreversible constriction of the visual field. The constriction of the visual field induced by vigabatrin is asymptomatic when it is restricted to the nasal quadrant, until it extends to more central areas. Furthermore, visual defects induced by vigabatrin are not limited to the constriction of the visual field but also includes dysfunction of central vision with a reduction of visual acuity, a loss of color discrimination and of contrast sensitivity. An arrest of a therapeutical treatment with vigabatrin allows a stabilization of the visual loss but very rarely induces any recovery.
However, because epileptic seizures are always very handicapping and may be lethal, active ingredients that increase the GABA levels, including vigabatrin, are still prescribed. Similarly, visual side effects were also described with many other anti-epileptic molecules blocking the GABA transaminase (valproate), increasing GABA levels by blocking GABA transporter (tiagabine), stimulating GABA synthesis and/or release (gabapentin, valproate, levetiracetam), or increasing GABA receptor activation (topiramate, felbamate, benzodiazepines like diazepam, clonazepam and clobazam or barbiturates like primidone and phenobarbitone).
There is thus a need in the art for substances or methods that would allow avoiding side effects that are caused to the human or animal organisms which are treated by anticonvulsive active ingredients that increase GABA levels or activate GABA receptors.
There is thus a need in the art for improved anticonvulsive, including anti-epileptic, pharmaceutical treatments based on anticonvulsive active ingredients, which would be endowed with reduced or no undesirable effects.